Review A global view of pulmonary hypertension Marius M Hoeper, Marc Humbert, Rogerio Souza, Majdy Idrees, Steven M Kawut, Karen Sliwa-Hahnle, Zhi-Cheng Jing, J Simon R Gibbs Lancet Respir Med 2016; 4: 306–322 Published Online March 11, 2016 http://dx.doi.org/10.1016/ S2213-2600(15)00543-3 See Editorial page 241 See Review page 323 See Online for podcast interview with Marius Hoeper Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany (Prof M M Hoeper MD); German Centre for Lung Research, Hannover, Germany (Prof M M Hoeper); Service de Pneumologie, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), Inserm UMR-S 999, Université Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France (Prof M Humbert MD); Pulmonary Department, Heart Institute, University of São Paolo Medical School, São Paolo, Brazil (Prof R Souza MD); Department of Pulmonary Medicine, Prince Sultan Medical Military City, Riyadh, Saudi Arabia (Prof M Idrees MD); Departments of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (Prof S M Kawut MD); Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa (Prof K Sliwa-Hahnle MD); Soweto Cardiovascular Research Unit, University of Witwatersrand, Johannesburg, South Africa (Prof K Sliwa-Hahnle); State Key Lab of Cardiovascular Disease, FuWai Hospital, National Centre for Cardiovascular Disease, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China (Prof Z-C Jing MD); and Department of Cardiology, National Heart and Lung Institute, Imperial College London, London, UK (Prof J S R Gibbs MD) Correspondence to: Prof Marius M Hoeper, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany [email protected] 306 Pulmonary hypertension is a substantial global health issue. All age groups are affected with rapidly growing importance in elderly people, particularly in countries with ageing populations. Present estimates suggest a pulmonary hypertension prevalence of about 1% of the global population, which increases up to 10% in individuals aged more than 65 years. In almost all parts of the world, left-sided heart and lung diseases have become the most frequent causes of pulmonary hypertension. About 80% of affected patients live in developing countries, where pulmonary hypertension is frequently associated with congenital heart disease and various infectious disorders, including schistosomiasis, HIV, and rheumatic heart disease. These forms of pulmonary hypertension occur predominantly in those younger than 65 years. Independently of the underlying disease, the development of pulmonary hypertension is associated with clinical deterioration and a substantially increased mortality risk. Global research efforts are needed to establish preventive strategies and treatments for the various types of pulmonary hypertension. Introduction Pulmonary hypertension is defined by a mean pulmonary artery pressure at rest of 25 mm Hg or more, measured by right heart catheterisation.1 According to pulmonary artery wedge pressure (PAWP), pulmonary hypertension can be subclassified as precapillary (PAWP ≤15 mm Hg) or postcapillary (PAWP >15 mm Hg). Based on pathophysiological, clinical, and therapeutic considerations, pulmonary hypertension is divided into five groups: pulmonary arterial hypertension; pulmonary hypertension due to left-sided heart disease; pulmonary hypertension due to lung disease or hypoxia; chronic thromboembolic pulmonary hypertension; and pulmonary hypertension with unclear or multifactorial mechanisms (figure 1). Although pulmonary hypertension has long been recognised to complicate many common diseases, especially left-sided heart disease and lung disease, most Key messages • Pulmonary hypertension is becoming an increasingly common global health issue • Pulmonary arterial hypertension, especially the idiopathic form, although still a rare disease with an incidence of 2–5 per million adults, is increasingly being diagnosed in elderly people • Globally, left-sided heart failure, particularly heart failure with preserved ejection fraction, is becoming a leading cause of pulmonary hypertension, probably affecting 5–10% of individuals aged 65 years or older • Lung disease, especially chronic obstructive pulmonary disease, is another leading cause of pulmonary hypertension in all parts of the world • Schistosomiasis, HIV infection, post-streptococcal rheumatic heart disease, and sickle cell disease are frequent causes of pulmonary hypertension in countries where these diseases are still endemic • The development of pulmonary hypertension is almost invariably associated with worsening symptoms and increased mortality, independent of the underlying disease researchers, clinicians, and the pharmaceutical industry have focused on certain forms of pulmonary hypertension, mainly pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Both entities are rare, leading to the belief that pulmonary hypertension in general is a rare condition. More recently, evidence suggests that pulmonary hypertension complicates various common diseases in which the development of pulmonary hypertension is almost invariably associated with aggravation of clinical symptoms and increased mortality. Additionally, the increasing age of populations worldwide is leading to a marked change in the distribution and phenotypes of patients presenting with pulmonary hypertension. A population-based study3 of 3381 participants in Rotterdam, Netherlands, reported echocardiographic signs suggestive of pulmonary hypertension in 2·6% of the overall population. The prevalence of echocardiographic signs of possible pulmonary hypertension was higher in older individuals (8·3% in those older than 85 years compared with 0·8% in those aged between 65 years and 70 years). We summarise the global incidence and prevalence of pulmonary hypertension and derive implications for health-care providers, policy makers, and future research strategies. Group 1—pulmonary arterial hypertension The pulmonary arterial hypertension group (figure 1) comprises patients with precapillary pulmonary hypertension due to distinct underlying disorders who share a similar pulmonary angioproliferative vasculopathy that predominantly affects the precapillary arterioles.4 The ensuing rise in the pulmonary vascular resistance leads to increased right ventricular afterload. Without effective therapeutic interventions, patients with pulmonary arterial hypertension eventually die from right heart failure.5 Idiopathic, heritable, or drug-induced, and associated with connective tissue disease or associated with portal pulmonary arterial hypertension Most contemporary pulmonary arterial hypertension registries (table 1) have been established in Europe and www.thelancet.com/respiratory Vol 4 April 2016 Review Pulmonary hypertension WHO group 1 Pulmonary arterial hypertension • Idiopathic • Heritable • Drug and toxin induced Associated with: • Connective tissue disease • HIV infection • Portal hypertension • Congenital heart disease • Schistosomiasis • WHO Group I’ (pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis) • WHO Group I’’ (persistent pulmonary hypertension of the newborn) WHO group 2 Pulmonary hypertension due to left-sided heart disease • Left ventricular systolic dysfunction • Left ventricular diastolic dysfunction • Valvular heart disease • Specific congenital abnormalities WHO group 3 Pulmonary hypertension due to lung disease or hypoxia • Chronic obstructive pulmonary disease • Interstitial lung diseases • Other mixed restrictive or obstructive lung disease • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental lung diseases WHO group 4 Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions WHO group 5 Pulmonary hypertension with multifactorial mechanisms • Chronic thromboembolic pulmonary hypertension • Other pulmonary artery obstructions (eg, angiosarcoma, other intravascular tumours, arteritis, congenital stenoses, and parasites) • Haematological disorders (eg, sickle cell disease) • Systemic disorders (eg, sarcoidosis, Langerhans cell granulomatosis) • Metabolic disorders (eg, Gaucher’s disease) • Others (eg, renal disease) Figure 1: Classification of pulmonary hypertension2 Modified with permission from Oxford University Press. the USA. At least for idiopathic or heritable pulmonary arterial hypertension, global variation is small between ethnicities and environmental factors such as urbanisation and exposure to drugs or toxins. Genetic causes of heritable pulmonary arterial hypertension have been identified worldwide, germline mutations in the gene coding for bone morphogenetic protein receptor type II (BMPR2) cause up to 80% of cases of familiar disease and 20% of cases of sporadic disease.27 The reported incidence of pulmonary arterial hypertension in the developed world is 1·1–7·6 per million adults per year; the prevalence of pulmonary arterial hypertension is 6·6–26·0 per million adults.10,12,18 Pulmonary arterial hypertension has generally been thought to affect predominantly younger individuals, mostly females.6 This consideration is particularly true for heritable pulmonary arterial hypertension, which affects twice as many females as males before the age of 50 years.28 Moreover, female sex is a risk factor for pulmonary arterial hypertension, yet females have better survival than males.29 Since pulmonary arterial hypertension has been deemed to be a disease affecting mostly young people, some registries restrict inclusion to patients 65–70 years or younger.10,11 More recent data from the USA and Europe suggest,17,21,23,30 however, that pulmonary arterial hypertension is now frequently diagnosed in older patients, ie, those 65 years and older, who often present with cardiovascular comorbidities. In the 2014 UK National Audit on Pulmonary Hypertension, the median age at the time of diagnosis of pulmonary arterial hypertension was 60 years and 29% of the patients were 70 years or older.22 In Germany in 2014, the mean age of www.thelancet.com/respiratory Vol 4 April 2016 patients newly diagnosed with idiopathic pulmonary arterial hypertension was 65 years.21 Older age has been identified as an independent risk factor for mortality in patients with pulmonary arterial hypertension.19,31,30 In developing countries, the average age of patients with idiopathic pulmonary arterial hypertension is younger than 40 years.23,24,32 These discrepancies are probably due to several factors, including differences in the overall population age between developed countries and developing countries, and presumably higher disease awareness as well as easier access to experienced diagnostic facilities in developed countries. In most pulmonary arterial hypertension registries from the USA and Europe, idiopathic pulmonary arterial hypertension was the most common subtype (50–60% of all cases), followed by pulmonary arterial hypertension associated with connective tissue disease, pulmonary arterial hypertension associated with congenital heart disease, and pulmonary arterial hypertension associated with portal hypertension (portopulmonary hypertension).12,14,18,33 In patients with pulmonary arterial hypertension associated with connective disease, systemic lupus erythematosus is the most common subtype in southeast Asia,24,34 whereas systemic sclerosis is the predominant underlying disease in the rest of the world.8,10,12,14,35 Portopulmonary hypertension is rare, even in areas where viral hepatitis is endemic.36–38 The crude estimate for the global incidence of pulmonary arterial hypertension (including only idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension associated with connective tissue disease, and portopulmonary hypertension) is about 5 million adults per year and a prevalence of about 307 Review Year of inclusion Number of participants Proportion of females (%) Age (years) Estimated incidence in the population (per million) Estimated prevalence in the population (per million) 1 year survival by incident patients (%) 3 year survival by incident patients (%) National Institutes of Health6,7 1981–85 187 59% 36 (15) ·· ·· 68% 48% Chicago registry8 1982–2006 578 77% 48 (14) ·· ·· 85% ·· Columbia University registry9 1994–2002 84 81% 42 (14) ·· ·· 87% 75% Scottish morbidity records*10 1986–2001 374 70% 52 (12) 7·6 ·· ·· ·· ·· 1·7 ·· ·· The International 1992–94 Primary Pulmonary Hypertension study, Belgium†11 24 26·0 ·· French registry‡5,12,13 2002 and 2003 674 65% 50 (15) 2·4 15·0 89% 55% REVEAL§14–17 2006 and 2007 2967 80% 50 (14) 2·0 10·6 91% 75% Spanish registry¶18 1998–2008 886 71% 45 (17) 3·7 16·0 89% 77% UK and Ireland registry||19 2001–09 482 70% 50 (17) 1·1 6·6 93% 73% Danish registry20 2000–12 134 58% 50 (21) ·· German registry21 2014 1754 62% 65 (16) 3·9 UK National Audit 201422 2004–14 2940 65% Female: 60 (··), male: 58 (··) ·· ·· 86% 73% 92% 68% ·· 86%|| 63%|| 25·9 Chinese registry23 1999–2004 72 71% 36 (12) ·· ·· 68% 39% Chinese registry24 2007–09 276 70% 33 (15)|| ·· ·· 92% 75% Brazilian registry25 2008–13 178 77% 46 (15) ·· ·· 93% 74% Saudi Arabian registry‡26 2009–12 107 63% 36 (9) ·· ·· 72% 57% Data are mean (SD). *Inclusion age was restricted to 16–65 years. †Inclusion age was restricted to 18–70 year. ‡Inclusion age was 18 years or older. §Inclusion age older than 3 months, only 16% of the patients were incident. ¶Inclusion age in inclusion criteria not stated. ||Only idiopathic, heritable, and drug-associated pulmonary arterial hypertension. Table 1: Data for the epidemiology and outcomes of pulmonary arterial hypertension reported from registries of various countries 15 per million adults. Hence, these disorders might affect about 35 000–100 000 individuals worldwide. Of note, these numbers do not include pulmonary arterial hypertension associated with congenital heart disease, schistosomiasis, and HIV infection, which play a prominent part in some areas of the world. Pulmonary arterial hypertension associated with congenital heart disease Congenital heart disease affects 0·8% of newborns, with some geographical variation.39 With increasing survival, the prevalence of congenital heart disease is now about 0·5 per 1000 adults, and 4–6% of these patients develop pulmonary arterial hypertension.40,41 On the basis of these numbers, the estimated global prevalence of pulmonary arterial hypertension due to congenital heart disease is about 25 people per million in the general population. Patients with pulmonary arterial hypertension associated with congenital heart disease tend to have a better survival than patients with idiopathic pulmonary arterial hypertension.15 However, compared with patients with congenital heart disease without pulmonary arterial hypertension, patients with 308 congenital heart disease and pulmonary arterial hypertension are more symptomatic and have at least a doubled mortality risk.42,43 Pulmonary arterial hypertension associated with infectious diseases Present estimates suggest that more than 200 million people worldwide are infected with species of Schistosoma.44 More than 85% of these patients live in Brazil and sub-Saharan Africa where the prevalence of infected individuals can exceed 50% in local populations.45,46 In Brazil, about 20–30% of patients treated in pulmonary hypertension clinics are infected with Schistosoma mansoni.25,47 Pulmonary arterial hypertension develops predominantly in patients with the hepatosplenic manifestation of the disease, which occurs in 4–8% of the patients with chronic schistosomiasis.44,48 A study from Brazil47 reported a prevalence of pulmonary arterial hypertension of 4·6% in patients with hepatosplenic schistosomiasis. Mortality in patients with schistosomiasis-associated pulmonary arterial hypertension is similar to mortality in patients with idiopathic pulmonary arterial hypertension.49 More www.thelancet.com/respiratory Vol 4 April 2016 Review than 270 000 people have been estimated to be affected by schistosomiasis-associated pulmonary arterial hypertension worldwide.47,50,51 This number might grossly overestimate the true prevalence of schistosomiasisassociated pulmonary arterial hypertension because reliable data are not available for Africa (predominantly Schistosoma mansoni and Schistosoma haematobium species) and southeast Asia (predominantly Schistosoma japonicum species). In these parts of the world, schistosomiasis might be much less frequently associated with pulmonary arterial hypertension than in Brazil but robust evidence is absent.52 The prevalence of pulmonary arterial hypertension in patients living with HIV infection is about 0·5% in Switzerland and France.53,54 In Europe and the Americas, HIV is a rare cause of pulmonary arterial hypertension, accounting for less than 10% of the patients enrolled in contemporary pulmonary arterial hypertension registries.12,14,18,25 Worldwide, about 30 million individuals are infected with HIV.55 If 0·5% of these patients develop pulmonary arterial hypertension, the global prevalence of pulmonary arterial hypertension due to HIV infection would be about 150 000 cases, possibly making HIV the most common infectious cause of pulmonary arterial hypertension. The greatest burden of HIV lies in subSaharan Africa where more than 20 million people were affected in 2013, and HIV prevalence exceeded 10% in some areas.55 Here, the prevalence of pulmonary arterial hypertension due to HIV might be up to 0·5 per 1000 individuals—ie, 20–50 times higher than the prevalence of all pulmonary arterial hypertension subtypes together in the developed world. However, these numbers are hypothetical and are not yet supported by published data. physician awareness of the disease, especially with respect to heart failure with preserved ejection fraction.57,63,65 Postcapillary pulmonary hypertension, either isolated or combined with a precapillary component,2,66 is a frequent complication of heart failure with preserved ejection fraction or with reduced ejection fraction, affecting at least 50% of these patients (table 2). In both populations, the development of pulmonary hypertension is associated with right ventricular dysfunction and at least a doubled mortality risk (table 2).59,60,67,71,77 The pandemic of left-sided heart disease is not confined to high-income countries but has already reached most parts of Asia, Africa, and Latin America.78,79 Recent studies from sub-Saharan Africa80–85 showed that patients admitted to the hospital for treatment of heart failure were younger than patients in the developed world but risk factors and underlying diseases were becoming similar, with hypertension being the most frequent underlying cause. Data from the Heart of Soweto Cohort86 suggest that pulmonary hypertension might be common in Africans living in an urban environment. From 5328 de-novo presentations to a single tertiary referral centre in South Africa, 2505 cases presented with heart failure and 697 (28%) were noted to have echocardiographic signs suggestive of pulmonary hypertension.86 Apart from concurrent left-sided heart disease (213 [31%] of 697 cases), several contributors to pulmonary hypertension were noted, including 179 (26%) cases of tuberculosis or chronic obstructive pulmonary disease (COPD) and 141 cases (20%) of suspected pulmonary arterial hypertension. In these cohorts, the presence of echocardiographic signs suggestive of pulmonary hypertension was a strong and independent predictor of mortality.80,87 Group 2—pulmonary hypertension due to left-sided heart disease Aortic stenosis In 2013, the Global Burden of Disease Study reported 61·7 million cases of heart failure worldwide, which represented almost a doubling since 1990.56 The leading causes of heart failure were ischaemic heart disease and hypertensive heart disease, followed by myocarditis, cardiomyopathies, and rheumatic heart disease.56 On the basis of estimates from the Framingham Heart Study,57 the lifetime risk of heart failure is about 20% in men and women living in the USA. Both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction affect predominantly elderly people.58–60 In Europe and the USA, more than 80% of patients with heart failure are 65 years of age and older.61 Over the past 30 years, survival has improved for patients with heart failure and reduced ejection fraction but not for patients with heart failure and preserved ejection fraction.58,62–64 The number of elderly patients diagnosed with heart failure is steadily growing, which is due not only to the rapid global rise in the number of people older than 65 years, but also due to the increasing www.thelancet.com/respiratory Vol 4 April 2016 The prevalence of aortic stenosis increases with age. In a population-based study from Norway,88 the prevalence of aortic stenosis was 1·3% in individuals aged 60–69 years and 9·8% in those who were 80–90 years old. The prevalence of severe aortic stenosis needing surgery was about 2% in the 80–90 year olds.88 Based on Medicare data,89 the adjusted incidence rates of patients 75–84 years old undergoing aortic valve replacement surgery increased from 125 per 100 000 in 1999 to 168 per 100 000 in 2011; the respective adjusted incidence rates of patients 85 years or older undergoing aortic valve replacement surgery increased from 48 per 100 000 in 1999 to 91 per 100 000 in 2011, indicating aortic stenosis is becoming an increasingly relevant problem, particularly in ageing populations. Several studies indicate that 50–70% of patients with severe aortic stenosis develop pulmonary hypertension and that the presence of pulmonary hypertension is associated with about a doubled increase in mortality risk (table 2).70,72–76 Overall, the left-sided heart diseases described previously affect mainly elderly people with a lifetime risk in ageing populations of 20% or higher. Based on the 309 Review Year of inclusion Ghio et al; Italy*67 1992–98 Number of Proportion participants of females (%) Age (years) Predominant population Proportion with pulmonary hypertension (%) Effect of pulmonary hypertension on survival 62% by right heart catheter† 10% increase in risk of death with each 5 mm Hg increase in PAPm (p<0·001) 379 15% 51 (10) Heart failure with reduced ejection fraction (left ventricular ejection fraction <35%) Grigioni et al; Italy68 1996–2003 196 27% 54 (9) Heart failure with reduced ·· ejection fraction (left ventricular ejection fraction 18–36%) Pulmonary hypertension at time of diagnosis associated with a relative risk of 2·3 for acute heart failure or death (p<0·001) Miller et al; Rochester, MN, USA69 2002–08 463 27% 57 (13) Heart failure with reduced ejection fraction Pulmonary hypertension at time of diagnosis associated with a hazard ratio of 2·2 for death (p<0·001), particularly in patients with a precapillary component Gerges et al; Austria70 1996–2003 ·· 63 (13) Heart failure with preserved 46% by right heart catheter (PAPm ejection fraction and heart ≥25 mm Hg) failure with reduced ejection fraction Presence of pulmonary hypertension associated with significantly worse survival, p<0·001, particularly in patients with combined precapillary and postcapillary pulmonary hypertension Lam et al; Olmsted County, MN, USA59 2003–05 244 55% 76 (13) PAPs >35 mm Hg by Heart failure with preserved ejection fraction echocardiography, in 83% of the patients (left ventricular ejection fraction ≥50%) Hazard ratio 1·3 per 10 mm Hg increase in PAPs (p<0·001) Bursi et al; Olmstedt County, MN, USA71 2003–10 1049 51% 76 (13) Heart failure with preserved PAPs >35 mm Hg by ejection fraction and heart echocardiography in 79% of the patients failure with reduced ejection fraction PAPs significantly associated with mortality (p<0·001) Kjaergaard et al; Denmark60 ·· 388 40% 75 (66–82) PAPs ≥39 mm Hg by Heart failure with preserved ejection fraction echocardiography in 49% of the patients and heart failure with reduced ejection fraction 9% increase in mortality per 5 mm Hg increase in PAPs (p<0·001) Barbash et al; Washington, DC, USA72 2007–13 415 53% 84 (8) Aortic stenosis, patients undergoing transcatheter aortic valve replacement PAPs >50 mm Hg by echocardiography in 59% of the patients, 35% had signs of right ventricular failure 30 day mortality 14·5% in patients with PAPs >50 mm Hg vs 7·4% in patients with PAPs ≤50 mm Hg (p=0·02); 1 year mortality 30·8% in patients with PAPs >50 mm Hg vs 21% in patients with PAPs ≤50 mm Hg (p=0·02) Cam et al; Cleveland, OH, USA73 2004–09 317 47% PAPm >25 mm Hg, 71 (12), PAPm>35 mm Hg, 75 (10) Aortic stenosis, right heart catheter before aortic valve replacement PAPm >25 mm Hg in 47% of the patients; PAPm >35 mm Hg in 11% of the patients ·· Roselli et al; Cleveland, OH, USA74 1996–2010 2385 45% 74 (10) Aortic stenosis, echo assessment of pulmonary hypertension before aortic valve replacement 74% echocardiography signs of pulmonary hypertension, 50% of patients had PAPs 35–50 mm Hg; 24% of patients had PAPs >50 mm Hg 5 year survival, 85% for PAPs <35 mm Hg, 77% for PAPs 35–50 mm Hg, 62% for PAPs >50 mm Hg (p<0·001) Ben-Dor et al; Washington, DC, USA75 2007–09 509 About 25% About 82 (··) Aortic stenosis 68% had signs of pulmonary hypertension by echocardiography, 34% of patients had PAPs 40–59 mm Hg; another 34% of patients had PAPs ≥60 mm Hg In a median follow-up of 202 days, mortality was 21·7% in PAPs <40 mm Hg, 39·3% in PAPs 40–49 mm, and 49·1% in PAPs ≥50 mm Hg in the (p<0·001) O’Sullivan et al; Switzerland76 2007–12 433 55% 82 (5) Aortic stenosis PAPm ≥25 mm Hg in 75% of the patients Higher 1 year mortality in patients with pulmonary hypertension, especially for combined precapillary and postcapillary disease compared with no pulmonary hypertension; hazard ratio 3·28; p=0·005 2351 73% by right heart catheter Data are mean (SD) or median (IQR). *Patients assessed for heart transplant. †Pulmonary hypertension was defined as PAPm >20 mm Hg. PAPm=mean pulmonary artery pressure. PAPs=systolic pulmonary artery pressure. Table 2: Studies assessing the prevalence and effect of pulmonary hypertension in heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and valvular heart disease by country and institution data in table 2, the lifetime risk of developing pulmonary hypertension due to left-sided heart disease may be 10% or higher. About 600 million people on the planet are 310 >65 years old.90 Hence, pulmonary hypertension due to left-sided heart disease might affect 30 million individuals older than 65 years old worldwide. www.thelancet.com/respiratory Vol 4 April 2016 Review Rheumatic heart disease Post-streptococcal rheumatic fever has become rare in developed countries but remains a leading cause of heart disease in the developing world, estimated to affect about 15 million individuals worldwide.91 The Global Rheumatic Heart Disease Registry,92 a prospective, international, multicentre, hospital-based study of characteristics, management, and outcome of rheumatic heart disease that enrolled 3323 participants from low-income and middle-income countries, showed that rheumatic heart disease affects predominantly young women, causes multivalvular disease and is associated with high rates of complications, such has heart failure. Echocardiographic signs suggestive of pulmonary hypertension were reported in 28·8% of these patients.92 In a study from southern India, the age-adjusted prevalence of rheumatic heart disease was 9·7 per 1000 and the mean age of the affected patients was 33 years.93 Echocardiographic signs suggestive of pulmonary hypertension were noted in 52% of these patients.93 Similar numbers were reported from Africa, where 53% of patients with newly diagnosed rheumatic heart disease presented with echocardiographic signs of pulmonary hypertension.94 Pulmonary hypertension and right ventricular failure have independent, incremental prognostic value and frequently exclude candidacy for surgery in patients with advanced rheumatic heart valve disease.95 Additionally, pulmonary hypertension complicates pregnancy in women with operated or not operated rheumatic heart disease contributing to increased maternal and fetal mortality.96 These data indicate that rheumatic heart disease is a major cause of pulmonary hypertension in some parts of the world, probably affecting between 3 million and 4 million individuals worldwide. However, these numbers need to be interpreted with caution because they are based almost entirely on echocardiographic assessments. Group 3—pulmonary hypertension due to lung disease or hypoxia selected populations of patients with advanced disease referred for evaluation of lung volume reduction surgery or lung transplantation. In these patient populations, the prevalence of pulmonary hypertension ranged from 30% to 50% (table 3).106,111,112,116 Some of the available population-based studies were completed more than 10 years ago and defined pulmonary hypertension as a mean pulmonary artery pressure of more than 20 mm Hg.105,106,113–115 The reported estimates of pulmonary hypertension prevalence (defined by a mean pulmonary artery pressure ≥25 mm Hg) in patients with COPD has ranged from 18% to 50% (table 3).107–110,111,112,116 Pulmonary hypertension is usually mild in this patient population. The proportion of patients with COPD and more severe pulmonary hypertension indicated by a mean pulmonary artery pressure of 35 mm Hg or more, ranges from 2% to 14% (table 3).106,108,110,112–114,116 Severe pulmonary hypertension in patients with COPD is often associated with other potential causes, such as left-sided heart disease or chronic thromboembolic disease.113 Irrespective of the populations under study, the presence of pulmonary hypertension was associated with more severe symptoms, reduced exercise capacity, and more frequent hospital admissions than in patients without pulmonary hypertension. Mortality was about twice as high in patients with COPD and pulmonary hypertension as in patients with COPD and normal pulmonary artery pressure, even when adjusted for other variables known to affect outcome, such as lung function variables, blood gases, or age (table 3).105,113,115,116 Assuming a global COPD prevalence (disease severity stage II or higher) of 10% in the 2·5 billion adults that are 40 years or older and estimating a pulmonary hypertension prevalence of 10% in these patients,117 about 25 million individuals aged 40 years or older might be affected worldwide by pulmonary hypertension due to COPD. Again, these numbers have to be interpreted with caution as they are based on assumptions rather than population-based studies. Chronic obstructive pulmonary disease COPD is the most common non-infectious lung disease worldwide.97 According to the Burden of Obstructive Lung Disease Initiative,98 the global prevalence of COPD GOLD stage II or higher is about 10% in adults 40 years or older and about 20% in adults 70 years or older. 99 Similar numbers have been reported from other studies implemented in Latin America, the Middle East, Africa, and Asia.100–103 A systematic review and meta-analysis of epidemiological studies of COPD published between 1990 and 2004 calculated a global pooled COPD prevalence in adults 40 years and older of 9–10% (GOLD ≥stage II, 5·5%), which increased to 14·2% in individuals aged 65 years or more.104 The prevalence of pulmonary hypertension in patients with COPD is difficult to estimate as most right heart catheter-based data come from highly www.thelancet.com/respiratory Vol 4 April 2016 Interstitial lung disease Among the interstitial lung diseases, idiopathic pulmonary fibrosis is by far the most widely studied, including idiopathic pulmonary fibrosis with the presence of pulmonary hypertension. The reported prevalence of idiopathic pulmonary fibrosis ranges from 2·9 per 100 000 in Japan to 500 per 100 000 in the USA.118–120 Idiopathic pulmonary fibrosis occurs predominantly in individuals older than 60 years and the global prevalence is increasing.120–122 Estimating the global prevalence of pulmonary hypertension in patients with idiopathic pulmonary fibrosis is hampered by similar restrictions to patients with COPD. Most catheter-based studied have been done in patients with advanced disease referred for evaluation of lung transplantation. In these studies, the prevalence 311 Review Year of inclusion Number of Proportion participants of females (%) Age (years) Lung function: Arterial blood gases: FEV1/FVC, or PaO2, PaCO2 (mm Hg) predicted FEV1 (%) Patients with pulmonary hypertension (%) Effect of pulmonary hypertension on survival 60 (range 36–82) FEV1/FVC 40% (11%) PAPm >20 mm Hg in 35·4%, PAPm >30 mm Hg in 9·7% 4 year survival 71·8% when PAPm <20 mm Hg vs 49·4% when PAPm >20 mm Hg (p<0·01) Weitzenblum et al; France105 1968–72 175 1% Scharf et al; USA106 ·· 120 39% 66 (6), evaluation for lung volume reduction surgery Predicted FEV1 27% 66 (10), (7%) 42 (6) PAPm >20 mm Hg in 91%, PAPm >35 mm Hg in 5% ·· Sims et al; USA107 1991–2003 362 53% 56 (5), evaluation for transplantation Predicted FEV1 20% (5%) 62 (12), 51 (10) pulmonary hypertension group PAPm ≥25 mm Hg and PAWP ≤15 mm Hg in 23% ·· Minai et al; USA108 ·· 797 35% 67 (6) Predicted FEV1 26% (7%) (pulmonary hypertension group) 61 (9), 43 (6) pulmonary hypertension group PAPm ≥25 mm Hg in 38%, severe pulmonary hypertension in 2·2%* ·· Cuttica et al; USA109 1997–2006 4930 54% 56 (6), pulmonary hypertension group, evaluation for transplantation Predicted FEV1 22% (10%) ·· PAPm ≥25 mm Hg and PAWP ≤15 mm Hg in 30% Adjusted hazard ratio for death associated with the presence of pulmonary hypertension 1·27 (95% CI 1·04–1·55) Portillo et al; Spain110 ·· 139 4% 63 (8) Predicted FEV1 41% (16%) 69 (12), 40 (6) PAPm ≥25 mm Hg in 18%, PAPm ≥35 mm Hg in 3% ·· Vizza et al; Italy111 1993–1995 168 62% 54 (6), evaluation for transplantation Predicted FEV1 20% (6%) 59 (12), 46 (11) PAPm ≥25 mm Hg in about 50% ·· Thabut et al; France112 1988–2002 215 21·4% 55 (··), evaluation for transplantation or LVRS Predicted FEV1 24·3% (··) 66 (13), 41 (7) lung volume reduction surgery cohort PAPm >25 mm Hg in 50·2%, PAPm >35 mm Hg in 13·5% ·· Chaouat et al; France113,114 1990–2002 998 10% 67 (62–68) Predicted FEV1 50% (44–56) 46 (41–53), 32 (28–37) PAPm >20 mm Hg in about 50%, PAPm ≥35 mm Hg in 5·8%, PAPm ≥40 mm Hg in 1% 3 year survival about 88% in patients with PAPm <20 mm Hg vs about 38% in patients with PAPm ≥40 mm Hg (p<0·01) OswaldMammosser et al; France115 1976–1992 84 10·7% 63 (··) FEV1/FVC 36% (11%) 52 (5), 45 (8) PAPm >20 mm Hg in 77%, PAPm >30 mm Hg in 37% 5 year survival 62·2% when PAPm ≤25 mm Hg vs 36·3% when PAPm >25 mm Hg (p<0·001) Andersen et al; Denmark116 1991–2010 409 61% 54 (7), evaluation for transplantation Predicted FEV 23% (7%) 63 (12), 49 (11) pulmonary hypertension group PAPm ≥25 mm Hg in 35·7%, PAPm ≥35 mm Hg in 3·9%, PAPm ≥40 mm Hg in 1·5% 5 year survival 63% when PAPm <25 mm Hg vs 37% when PAPm ≥25 mm Hg (p=0·016) 63 (10), 40 (6) Data are mean (SD) or median (IQR). FEV1=forced expiratory volume in the first second. FVC=forced vital capacity. PaO2=partial pressure of oxygen in arterial blood. PaCO2=partial pressure of carbon dioxide in arterial blood. PAPm=mean pulmonary arterial pressure. PAWP=pulmonary arterial wedge pressure. *Severe pulmonary was defined by a PAPm ≥35 mm Hg or a PAPm ≥25 mm Hg with pulmonary vascular resistance >480 dyn·s·cm−5 or cardiac index <2 L/min per m². Table 3: Right heart catheter-based studies on pulmonary hypertension in patients with chronic obstructive pulmonary disease of pulmonary hypertension in patients with idiopathic pulmonary fibrosis ranged from 29% to 77% (table 4).123,125,126,127 In two cohorts of patients with idiopathic pulmonary fibrosis from Japan,128,129 the prevalence of pulmonary hypertension was 8% and 15%. In a clinical trial with ambrisentan in patients with idiopathic pulmonary fibrosis with mild or moderate lung volume restriction, the prevalence of precapillary pulmonary hypertension was 14% and 5% of patients had postcapillary pulmonary hypertension.131 Cross-sectional studies might, however, underestimate the true lifetime risk of pulmonary hypertension in this 312 patient population. This theory is supported by the work of Nathan and colleagues127 who completed a longitudinal assessment of pulmonary hypertension in patients with idiopathic pulmonary fibrosis listed for lung transplantation. At the time of admission to the waiting list, 39% of the patients had pulmonary hypertension. An average of 8 months later, at the time of transplant, this figure had risen to 86%.127 By contrast, no significant change was noted in the mean pulmonary artery pressure after 12 months in the clinical trial with ambrisentan in patients with mild or moderate lung volume restriction.131 www.thelancet.com/respiratory Vol 4 April 2016 Review Year of inclusion Number of Proportion Age (years) participants of females (%) Lung function: Arterial blood Patients with predicted FVC gases: PaO2, pulmonary (%) PaCO2 (mm Hg) hypertension (%) Effect of pulmonary hypertension on survival 1 year survival 95% in patients with PAPm <25 mm Hg vs 71% in patients with PAPm ≥25 mm Hg (p<0·001) Idiopathic pulmonary fibrosis Lettieri et al, USA123 1998–2004 Patel et al, USA124 2004–05 Shorr et al, USA125 1995–2004 Rivera-Lebron et al, USA126 79 36%* 55 (4)* transplantation evaluation 49% (11%)* ·· PAPm ≥25 mm Hg in 31·6% ·· ·· ·· ·· PAPm ≥25 mm Hg and ·· PAWP ≤15 mm Hg in 28% 2525 37%* 53 (9) transplantation evaluation 48% (17%)* ·· (··), 41 (7)* PAPm ≥25 mm Hg in 46·1%, PAPm >40 mm Hg in 9·1% 2005–10 135 27% 58 (7) transplantation evaluation 51% (15%) ·· PAPm ≥25 mm Hg and Adjusted hazard ratio for each 10 mm Hg increase in PAPm, 1·3 PAWP ≤15 mm Hg in (95% CI 1·0–1·8) 29% Nathan et al, USA127 2000–05 44 22% 57 (7) transplantation evaluation 50% (16%) ·· Baseline PAPm ≥25 mm Hg in 38·6%; in 86·4% pulmonary hypertension at time of transplantation ·· Hamada et al, Japan128 1991–2004 78 14% 63 (9)* 71% (20%)* 67 (12),* 37 (3)* PAPm ≥25 mm Hg in 8·1% 5 year survival 62% with PAPm <17 mm Hg vs 17% with PAPm >17 mm Hg (p<0·001) Kimura et al, Japan129 2001–09 101 16% 65 (8) 70% (20%) 80 (12), ·· (··) 14·9% had a PAPm >25 mm Hg; 3·9% had a PAPm >35 mm Hg 3 year survival about 60% in patients with PAPm <25 mm Hg vs 20% in patients with PAPm ≥25 mm Hg (p<0·001) Gläser et al, Germany130 2004–11 135 39% 64 (56–72) 56% (43–67%; (pulmonary hypertension group) ·· PAPm ≥25 mm Hg in 54% Hazard ratio for death associated with the presence of pulmonary hypertension 1·07 (95% CI 1·04–1·11) Raghu et al, 2009–10 ARTEMIS-IPF 131 study (global) 488 31% 68 (6)* 67% (12%) ·· PAPm ≥25 mm Hg and ·· PAWP ≤15 mm Hg in 14% 66 42% 57 (12) transplantation evaluation 68% (23%) 66 (17), 39 (7) PAPm ≥25 mm Hg in 76%; PAPm ≥35 mm Hg in 42% Odds ratio for mortality 3·0 when PAPm ≥25 mm Hg (p=0·18) 144 71% 59 (15)* 59% (20%) ·· PAPm ≥25 mm Hg in 29% ·· 376 ·· Diffuse parenchymal lung disease Corte et al, UK132 1987–07 Various interstitial lung diseases Alhamad et al, Saudi Arabia133 2009–12 Data are mean (SD) or median (IQR). FVC=forced vital capacity. PaO2=partial pressure of oxygen in arterial blood. PaCO2=partial pressure of carbon dioxide in arterial blood. PAPm=mean pulmonary arterial pressure. PAWP=pulmonary artery wedge pressure. *Patients with pulmonary hypertension. Table 4: Right heart catheter-based studies on pulmonary hypertension in patients with interstitial lung disease Assuming an idiopathic pulmonary fibrosis prevalence of 500 per 100 000 individuals 65 years or older, as suggested by Raghu and colleagues,120 and a conservative estimate of pulmonary hypertension of 10% among these patients, the global figure of patients affected by pulmonary hypertension due to idiopathic pulmonary fibrosis would be about 300 000 individuals older than 65 years. These assumptions do not include other forms of interstitial lung disease, which might also be complicated by the development of pulmonary hypertension. The effect of pulmonary hypertension on the survival of patients with idiopathic pulmonary fibrosis is substantial. www.thelancet.com/respiratory Vol 4 April 2016 Several studies have shown that the mortality risk was about three times higher in patients with idiopathic pulmonary fibrosis and pulmonary hypertension compared with patients with idiopathic pulmonary fibrosis without pulmonary hypertension.123,128,129 Pulmonary hypertension due to high altitude More than 140 million people live above 2500 m from sea level and are exposed to chronic hypoxia, particularly in the Andes and Himalayas.134 Some of these individuals develop symptomatic pulmonary hypertension,135,136 but because of the scarcity of systematic studies, the 313 Review prevalence of pulmonary hypertension in people living at high altitude is difficult to estimate. The same is true for the clinical implications because pulmonary hypertension is a physiological result of exposure to chronic hypoxia, at least to some extent.137,138 Pulmonary hypertension proportional to hypoxaemia and haematocrit is a complication of chronic mountain sickness.137 High altitude pulmonary hypertension might affect a substantial number of individuals but insufficient data are available to estimate its clinical burden. Group 4—chronic thromboembolic pulmonary hypertension In a detailed review on chronic thromboembolic pulmonary hypertension,139 the incidence and prevalence of this disease are largely unknown. Studies in patients who survived an episode of acute pulmonary embolism have reported that 1·0–8·8% of them eventually developed chronic thromboembolic pulmonary hypertension.140–143 The higher estimates are likely to be an over-representation. In the USA, the annual incidence of acute pulmonary embolism is about 100 in 100 000 adults, increasing with age.144 Individuals aged 25–35 years have a pulmonary embolism incidence of 30 per 100 000 per year, whereas the respective rates in individuals aged 70–79 years are 300–500 per 100 000 per year.144 If 1% of these patients develop chronic thromboembolic pulmonary hypertension, the expected annual incidence would be at least one in 100 000 adults. In the USA, this number would result in about 2500 new cases per year. By contrast, the number of patients undergoing pulmonary endarterectomy (the preferred treatment for chronic thromboembolic pulmonary hypertension) in the USA is about ten times lower.145 Estimates of the prevalence of chronic thromboembolic pulmonary hypertension are further restricted by the fact that about 25% of these patients have no history of acute pulmonary embolism.146 Two pulmonary hypertension registries, one from Spain and one from the UK,18,147 have assessed the incidence of patients with an established diagnosis of chronic thromboembolic pulmonary hypertension. These registries reported annual chronic thromboembolic pulmonary hypertension incidence rates of 0·9 per million in Spain and 1·75 per million in the UK—ie, about a tenth of that expected from the assumptions made previously in this Review (table 5).18,147 Recent data from Germany reported an annual chronic thromboembolic pulmonary hypertension incidence of 4·0 per million adults per year (Hoeper MM, unpublished data). The global prevalence of chronic thromboembolic pulmonary hypertension is difficult to calculate as many of these patients undergo pulmonary endarterectomy surgery (at least in developed countries), which is curative in many cases.145,146,148 Group 5—pulmonary hypertension with unclear multifactorial mechanisms Group 5 comprises various diseases that are often accompanied by pulmonary hypertension, which is characterised by unclear and multifactorial underlying mechanisms. One example is chronic renal failure, in which pulmonary hypertension is being increasingly recognised as an important medical issue. Echocardiography-based estimates of pulmonary hypertension prevalence in patients with end-stage renal disease range from 20% to 50%.149–151 The pathogenesis of pulmonary hypertension in these patients is complex. Most patients with end-stage renal disease have various comorbidities, including a high rate of systolic or diastolic heart failure. Anaemia, fluid overload, and arteriovenous fistulae might be additional factors contributing to the development of pulmonary hypertension.149,150 Pulmonary hypertension is also identified in patients with systemic disorders such as sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, and neurofibromatosis, as well as in metabolic disorders such as Gaucher’s disease or glycogen storage disease, and in patients with haemaglobinopathies.152–159 Although pulmonary hypertension is common in some of these diseases, most of them do not contribute substantially to the Number of participants (enrolled) Proportion of females (%) Age (years) Estimated Estimated prevalence (per incidence (per 1 million adults) 1 million adults) 1 year survival 3 year survival Spanish registry18 1998–2008 162 60% 61 (15) 0·9 3·2 93% (mostly prevalent patients) 75% (mostly prevalent patients) UK147 2001–06 469 56%* 60 (14)* 1·75 ·· 82%* 70%* Germany† 2014 272 49% 68 (··) 4·0 ·· ·· ·· UK National Audit22‡ 2009–14 684 (operated), 53% (operated), 69 (··; operated), 501 (non-operated) 48% (non-operated) 63 (··; non-operated) ·· 2·2 (for all chronic thromboembolic pulmonary hypertension) 98% (operated), 90% (operated), 70% 88% (non-operated) (non-operated) Year of inclusion Data are mean (SD). *Nonsurgical cases. †Hoeper MM, unpublished data. ‡Participants were patients with chronic thromboembolic pulmonary hypertension who either had an operation or did not. Table 5: Chronic thromboembolic pulmonary hypertension 314 www.thelancet.com/respiratory Vol 4 April 2016 Review global burden of pulmonary hypertension because of their rarity. An important exception is pulmonary hypertension associated with haemoglobinopathies. Pulmonary hypertension associated with haemoglobinopathies According to WHO estimates, 20–25 million individuals worldwide are affected by homozygous sickle cell disease, most of them living in sub-Saharan Africa, the Middle East, and India.160–163 Echocardiographic signs suggestive of pulmonary hypertension are reported in 20–40% of these patients.160,164,165 These numbers need to be interpreted with great caution as several studies reported that the positive predictive value of echocardiography is particularly low in this patient population.165–167 The prevalence of pulmonary hypertension in patients with sickle cell disease confirmed by right heart catheterisation was 6–10%,165–167 resulting in an estimated 1·0–2·5 million individuals affected by pulmonary hypertension due to sickle cell disease worldwide. Most of these patients show a unique haemodynamic profile with mildly elevated pulmonary artery pressures, elevated right-sided and left-sided filling pressures, high cardiac output, and a normal or mildly elevated pulmonary vascular resistance.165,168 Hence, pulmonary hypertension in patients with sickle cell disease most often presents in a state of high cardiac output failure rather than a state of low cardiac output as usually encountered in patients with pulmonary arterial hypertension,169 although a few patients do have low cardiac output. The prevalence of pulmonary hypertension in patients with sickle cell disease increases with age and is associated with more pronounced anaemia, haemolysis, and renal dysfunction.164,165,167 Additionally, the presence of pulmonary hypertension in patients with sickle cell disease is associated with impaired functional capacity and an increased risk of death, which was reported to be at least twice as high as in patients with sickle cell disease without pulmonary hypertension.164–168,170 Thalassaemia and spherocytosis are common haemoglobinopathies, but the associated risk of pulmonary hypertension is unclear. Echocardiographic signs suggestive of pulmonary hypertension have been reported in 10–79% of patients with β-thalassaemia,171,172 but the catheter-based pulmonary hypertension prevalence based on a multicentre cross-sectional study was 2·1%.173 Some reports suggest that pulmonary hypertension is more common in patients with thalassaemia intermedia,173–175 although pulmonary hypertension seems rare in well transfused patients with thalassaemia major.176,177 Pulmonary hypertension seems to be rare in patients with spherocytosis and seems to be linked to splenectomy and subsequent pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension rather than to the underlying disease.178,179 Heart failure (associated pulmonary hypertension) Moderate to severe chronic obstructive pulmonary disease* (associated pulmonary hypertension) HIV (associated pulmonary hypertension) Schistosomiasis (associated pulmonary hypertension) Rheumatic heart disease (associated pulmonary hypertension) Sickle cell disease (associated pulmonary hypertension) Worldwide 61 million (30·0 million) 250 million (25 million) 30·0 million (150 000) 200 million (unclear, except for some countries in Latin America) 15·0 million (3·75 million) 20·0 million (2 million) Europe, Australia, and New Zealand 8 million (4·0 million) 40 million (4 million) 1·0 million (5000) Rare, only by travel and migration (rare) Rare, except for the Indigenous populations of Australia and New Zealand (··) 100 000 (10 000) North America 7 million (3·5 million) 30 million (3 million) 1·1 million (5500) Rare, only by travel and migration (··) Rare (··) 80 000 (8000) Latin America and the Caribbean 5 million (2·5 million) 20 million (2 million) 1·6 million (8000) 10 million (13 000) 800 000 (200 000) 100 000 (10 000) Asia including Oceania (except Australia and New Zealand) 30 million (15·0 million) 110 million (11 million) 6·0 million (30 000) 10 million 6·5 million (unclear, probably rare) (1·63 million) 7·5 million, mostly India (750 000, mostly India) Africa (except northern Africa) 8 million (4·0 million) 30 million (3 million) 20·0 million (100 000) 170 million 6·5 million (unclear, probably rare) (1·3 million) 12·0 million (1·2 million) Northern Africa and Middle East 5 million (2·5 million) 20 million (2 million) 0·4 million (2000) 10 million 1·0 million (unclear, probably rare) (250 000) 0·5 million (50 000) *Moderate to severe was not used uniformly in all studies but usually refers to GOLD II–IV. Table 6: Crude estimates of the global and regional numbers of patients with pulmonary hypertension associated with the most frequent underlying disorders www.thelancet.com/respiratory Vol 4 April 2016 315 Review A 4% 5% 48% 45% 48% 5% 5% 6% 4% 5% 50% Europe 40% North America 50% 40% 45% Asia Middle East 10% 1% 9% 5% 45% 10% 30% 40% 50% Africa South America Left-sided heart disease Lung disease Rheumatic heart disease Sickle cell disease HIV Other 5% 45% 50% Australia B 11% 5% 2% 11% 10% 3% 27% 55% 20% 56% Europe North America 27% 40% 38% 3% 15% 55% 15% 2% Middle East 35% 30% 20% 30% 10% 10% 25% 5% South America Idiopathic Connective tissue disease HIV Portal hypertension Congenital heart disease Schistosomiasis 5% Asia 5% 25% Africa 5% 5% 2% 11% 27% 55% Australia Figure 2: Estimated global distribution of the most prevalent forms of (A) pulmonary hypertension and (B) pulmonary arterial hypertension Interpretation should be done with caution as most of the underlying evidence has been derived from populations at risk for pulmonary hypertension and echocardiography data rather than from population-based studies involving right heart catheterisation. Data from the developing world are particularly sparse. Additionally, variations exist within the world regions. In Latin America, for instance, schistosomiasis highly prevalent in Brazil, Venezuela, and the Caribbean, but not in other countries. Schistosomiasis is also prevalent in sub-Saharan Africa and Southeast Asia, but there is almost no data on the association between schistosomiasis and pulmonary arterial hypertension from these areas. HIV is not evenly distributed in Africa and is particularly frequent in some areas of sub-Saharan Africa. Limitations of studies of pulmonary hypertension The epidemiology of pulmonary hypertension is much more difficult to study than the epidemiology of systemic hypertension because a reliable diagnosis requires right heart catheterisation, which is an invasive procedure. Therefore, large-scale population-based studies have to rely on echocardiography because invasive tests for epidemiological studies would be neither ethical nor 316 feasible. The interpretation of these data must take into account that echocardiography is not a reliable method to diagnose pulmonary hypertension. Several catheter-based studies have been done in patients at risk for pulmonary arterial hypertension and in patients with left-sided heart disease and chronic lung disease. The results of these studies have been largely consistent, therefore confirming each other and also to a large extent, confirming studies on the basis of echocardiography, www.thelancet.com/respiratory Vol 4 April 2016 Review indicating some reliability and reproducibility of the available data (tables 2–4). Patients assessed by right heart catheterisation represent those with symptoms or some indication for evaluation, so that there are very few true screening studies of pulmonary hypertension. Most studies come from academic centres offering advanced treatments, such as transplantation, so that the characteristics of the patients under study might not be generalisable to the population at large. Additionally, almost all studies on the prevalence of pulmonary hypertension were cross-sectional by design. Longitudinal studies are needed to assess the true lifetime risk of various disorders associated with pulmonary hypertension. More uncertainties come from those types of pulmonary hypertension that occur predominantly in lesser-developed parts of the world, such as those reported in patients with schistosomiasis, HIV infection, rheumatic fever, or sickle cell disease. Any estimates of the incidence, prevalence, and effect of these forms of pulmonary hypertension have to be interpreted with great caution. The same is true for prevalence estimates of major diseases, such as left-sided heart failure and lung disease in the developing world, which are often based on clinical symptoms alone rather than on validated diagnostic tests. Despite these uncertainties, a consistent finding of almost all studies was the observation that the development of pulmonary hypertension is associated with worsening symptoms and shortened survival, independent of the underlying disease. The causes and mechanisms leading to death are enigmatic. Whether pulmonary hypertension is causative for adverse outcomes in most heart and lung disease is not clear; attempts to treat pulmonary hypertension in these disorders have not resulted in clinical benefit. Therefore, patients might die with pulmonary hypertension rather than as a result of the disorder. In most of the diseases discussed in this Review, to what extent pulmonary hypertension and right heart failure contribute to excess mortality is unclear. Importantly, present pulmonary hypertension guidelines state that the use of pulmonary arterial hypertension approved treatments is not recommended in patients with pulmonary hypertension due to left-sided heart disease or lung disease.2,66 Public health implications and conclusions Pulmonary hypertension is an under-recognised global health issue and is by no means rare. In economically developed countries, left-sided heart disease and lung disease are by far the most common causes of pulmonary hypertension (table 6, figure 2). About 80% of patients with pulmonary hypertension live in the developing world, where heart disease and lung disease have become the most frequent causes of pulmonary hypertension, but other disorders such as schistosomiasis, rheumatic heart disease, HIV, or sickle cell disease continue to play an important part (table 6, figure 2). Hence, in industrialised countries, pulmonary hypertension affects www.thelancet.com/respiratory Vol 4 April 2016 Search strategy and selection criteria References for this Review were identified through searches of PubMed, until Aug 31, 2015, by use of various combinations of the terms “pulmonary hypertension”, “lung disease”, “heart failure”, “aortic stenosis”, “chronic obstructive lung disease”, “pulmonary fibrosis”, “left heart disease”, “renal disease”, human immunodeficiency virus”, “schistosomiasis”, “rheumatic heart disease”, “registry”, “high altitude”, “epidemiology”, “incidence”, “prevalence”, “mortality”, and “phenotype”. Relevant articles were identified by MMH and JSRG. These articles were retrieved in full and were reviewed for content. Additional relevant references cited in those articles were added, as were relevant references provided by the other authors. Articles published in English, French, Spanish, Portuguese, Chinese, and German were considered. All searches and data analyses were restricted to studies of adults. We focused primarily on studies with right heart catheterisation for the diagnosis of pulmonary hypertension but also considered studies in which the presence of pulmonary hypertension was estimated by echocardiography, especially in areas where a paucity of right heart catheterisation data was available and whenever large populations of more than 100 patients were studied. mainly elderly people whereas mostly young people are diagnosed in the developing world. Preventive strategies and effective treatments have been or are being implemented for HIV infection, schistosomiasis, and rheumatic fever, which will affect the incidence of pulmonary hypertension associated with these disorders. At the same time, an increase in the global prevalence of left-sided heart disease and lung disease will continue, and pulmonary hypertension associated with these disorders will be mainly driven by a worldwide increase in life expectancy. In 2015, about 600 million people globally were 65 years or older with a projected number of 700 million for 2020 and 1·6 billion for 2050.180 For 2015, we estimate that up to 50–70 million individuals—almost 1% of all people—were affected by pulmonary hypertension worldwide. This figure is expected to rise continuously over the next few decades as the global population enlarges and ages. With increasing life expectancy, individuals who reach the age of 40 might have a lifetime risk of one in ten of developing pulmonary hypertension. This risk is similar to the one in ten lifetime risk of developing COPD,104 or to the one in eight remaining lifetime risk for breast cancer in women of the same age.181 Globally, prevention strategies aimed at reducing smoking, particulate matter and household air pollution, hypertension, diabetes, and obesity will have a major role in reducing heart failure and lung disease, which might eventually contribute to reducing the prevalence of some forms of pulmonary hypertension. Effective treatments have been developed for some of the rare forms of pulmonary hypertension, especially pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.139,182 No treatments directed at the pulmonary circulation have yet proven efficacious for most of the remaining much more frequent forms of pulmonary hypertension in which treatment is that of the underlying disease. Hence, clinical studies and registries are needed to further 317 Review elucidate the effect of pulmonary hypertension in the various conditions discussed in this Review and to establish whether preventive strategies and treatments targeting pulmonary hypertension will affect the morbidity and mortality that accompany this disorder. 13 Declaration of interests RS received personal fees from Actelion, Bayer, GlaxoSmithKline, and Pfizer, outside of this Review. SMK received grants from NIH; non-financial support from American College of Chest Physicians and American Thoracic Society; personal fees from European Respiratory Journal; grants to his institution for continuing medical education from Actelion, United Therapeutics, Gilead, Merck, Lung Biotech, Ikaria, Pulmonary Hypertension Association, GeNO, and Bayer, outside of this Review; and grants to his institution for research from Actelion, Gilead, and GeNO, outside of this Review. MMH received personal fees from Actelion, Bayer, GlaxoSmithKline, and Pfizer. Z-CJ received personal fees from Actelion, Bayer, Pfizer, and United Therapeutics. MH received grants and personal fees from Actelion, Bayer, GlaxoSmithKline, and Pfizer. JSRG received grants and personal fees from Actelion, Bayer, and GlaxoSmithKline, and United Therapeutics personal fees from Gilead, Novartis, and Pfizer, and grants from Amco, outside of this Review. KS-H and MI declare no competing interests. 15 Acknowledgments We thank Ms Aleksandra Graw, Hannover Medical School, for designing the figures. This Review is independent of any influence from pharmaceutical companies and has been written by the authors themselves without any third-party support. References 1 Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25 suppl): D42–50. 2 Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37: 67–119. 3 Moreira EM, Gall H, Leening MJ, et al. Prevalence of pulmonary hypertension in the general population: the Rotterdam study. PLoS One 2015; 10: e0130072. 4 Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25 suppl): D4–12. 5 Humbert M, Sitbon O, Yaïci A, et al, and the French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36: 549–55. 6 Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107: 216–23. 7 D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343–49. 8 Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 2007; 30: 1103–10. 9 Kawut SM, Horn EM, Berekashvili KK, et al. New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol 2005; 95: 199–203. 10 Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007; 30: 104–09. 11 Abenhaim L, Moride Y, Brenot F, et al, and the International Primary Pulmonary Hypertension Study Group. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–16. 12 Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173: 1023–30. 318 14 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010; 122: 156–63. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010; 137: 376–87. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012; 142: 448–56. McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol 2013; 62 (25 suppl): D51–59. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest 2011; 139: 128–37. Escribano-Subias P, Blanco I, López-Meseguer M, et al, and the REHAP investigators. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J 2012; 40: 596–603. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186: 790–96. Korsholm K, Andersen A, Kirkfeldt RE, Hansen KN, Mellemkjaer S, Nielsen-Kudsk JE. Survival in an incident cohort of patients with pulmonary arterial hypertension in Denmark. Pulm Circ 2015; 5: 364–69. Hoeper MM, Huscher D, Pittrow D. Incidence and prevalence of pulmonary arterial hypertension in Germany. Int J Cardiol 2016; 203: 612–13. Health and Social Care Information Centre. Fifth annual report: key findings from the National Audit of Pulmonary Hypertension of the UK, Channel Islands, Gibraltar and Isle of Man. Report for the audit period April 2013–March 2014. Jing ZC, Xu XQ, Han ZY, et al. Registry and survival study in Chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest 2007; 132: 373–79. Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest 2011; 140: 301–09. Alves JL Jr, Gavilanes F, Jardim C, et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest 2015; 147: 495–501. Idrees M, Alnajashi K, Abdulhameed J, et al, and the Registry Taskforce SAPH. Saudi experience in the management of pulmonary arterial hypertension; the outcome of PAH therapy with the exclusion of chronic parenteral prostacyclin. Ann Thorac Med 2015; 10: 204–11. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62 (25 suppl): D13–21. Girerd B, Montani D, Eyries M, et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res 2010; 11: 73. Ventetuolo CE, Praestgaard A, Palevsky HI, Klinger JR, Halpern SD, Kawut SM. Sex and haemodynamics in pulmonary arterial hypertension. Eur Respir J 2014; 43: 523–30. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol 2013; 168: 871–80. Benza RL, Gomberg-Maitland M, Naeije R, Arneson CP, Lang IM. Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials. J Heart Lung Transplant 2011; 30: 982–89. Idrees M, Al-Najashi K, Khan A, et al, and the SAPH Registry Taskforce. Pulmonary arterial hypertension in Saudi Arabia: Patients’ clinical and physiological characteristics and hemodynamic parameters. A single center experience. Ann Thorac Med 2014; 9: 209–15. www.thelancet.com/respiratory Vol 4 April 2016 Review 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation 2014; 129: 57–65. Hao YJ, Jiang X, Zhou W, et al. Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients. Eur Respir J 2014; 44: 963–72. Coghlan JG, Denton CP, Grünig E, et al, and the DETECT study group. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014; 73: 1340–49. Al-Harbi A, Abdullah K, Al-Abdulkareem A, Alghamdi A, Al-Jahdali H. Prevalence of portopulmonary hypertension among liver transplant candidates in a region highly endemic for viral hepatitis. Ann Transplant 2014; 19: 1–5. Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: Results from a 10-year screening algorithm. Hepatology 2006; 44: 1502–10. Kawut SM, Krowka MJ, Trotter JF, et al, and the Pulmonary Vascular Complications of Liver Disease Study Group. Clinical risk factors for portopulmonary hypertension. Hepatology 2008; 48: 196–203. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58: 2241–47. Marelli AJ, Ionescu-Ittu R, Mackie AS, Guo L, Dendukuri N, Kaouache M. Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation 2014; 130: 749–56. Duffels MG, Engelfriet PM, Berger RM, et al. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. Int J Cardiol 2007; 120: 198–204. Lowe BS, Therrien J, Ionescu-Ittu R, Pilote L, Martucci G, Marelli AJ. Diagnosis of pulmonary hypertension in the congenital heart disease adult population impact on outcomes. J Am Coll Cardiol 2011; 58: 538–46. Verheugt CL, Uiterwaal CS, van der Velde ET, et al. Mortality in adult congenital heart disease. Eur Heart J 2010; 31: 1220–29. Ross AG, Bartley PB, Sleigh AC, et al. Schistosomiasis. N Engl J Med 2002; 346: 1212–20. Chitsulo L, Engels D, Montresor A, Savioli L. The global status of schistosomiasis and its control. Acta Trop 2000; 77: 41–51. Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. Lancet 2014; 383: 2253–64. Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 2009; 119: 1518–23. Papamatheakis DG, Mocumbi AO, Kim NH, Mandel J. Schistosomiasis-associated pulmonary hypertension. Pulm Circ 2014; 4: 596–611. dos Santos Fernandes CJ, Jardim CV, Hovnanian A, et al. Survival in schistosomiasis-associated pulmonary arterial hypertension. J Am Coll Cardiol 2010; 56: 715–20. de Cleva R, Herman P, Pugliese V, et al. Prevalence of pulmonary hypertension in patients with hepatosplenic mansonic schistosomiasis—prospective study. Hepatogastroenterology 2003; 50: 2028–30. Bertrand E, Dalger J, Ramiara JP, Renambot J, Attia Y. Bilharzial pulmonary arterial hypertension. Clinical and hemodynamic study in 37 patients. Arch Mal Coeur Vaiss 1978; 71: 216–21 (in French). Watt G, Long GW, Calubaquib C, Ranoa CP. Cardiopulmonary involvement rare in severe Schistosoma japonicum infection. Trop Geogr Med 1986; 38: 233–39. Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 1991; 100: 1268–71. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008; 177: 108–13. Murray CJ, Ortblad KF, Guinovart C, et al. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 1005–70. www.thelancet.com/respiratory Vol 4 April 2016 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 386: 743–800. Lloyd-Jones DM, Larson MG, Leip EP, et al, and the Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 2002; 106: 3068–72. Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA 2006; 296: 2209–16. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53: 1119–26. Kjaergaard J, Akkan D, Iversen KK, et al. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol 2007; 99: 1146–50. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 2011; 8: 30–41. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004; 292: 344–50. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251–59. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–69. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011; 123: 2006–14. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 903–75. Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001; 37: 183–88. Grigioni F, Potena L, Galiè N, et al. Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure. J Heart Lung Transplant 2006; 25: 1241–46. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail 2013; 1: 290–99. Gerges C, Gerges M, Lang MB, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest 2013; 143: 758–66. Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and death in heart failure: a community study. J Am Coll Cardiol 2012; 59: 222–31. Barbash IM, Escarcega RO, Minha S, et al. Prevalence and impact of pulmonary hypertension on patients with aortic stenosis who underwent transcatheter aortic valve replacement. Am J Cardiol 2015; 115: 1435–42. Cam A, Goel SS, Agarwal S, et al. Prognostic implications of pulmonary hypertension in patients with severe aortic stenosis. J Thorac Cardiovasc Surg 2011; 142: 800–08. Roselli EE, Abdel Azim A, Houghtaling PL, Jaber WA, Blackstone EH. Pulmonary hypertension is associated with worse early and late outcomes after aortic valve replacement: implications for transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2012; 144: 1067–74.e2. Ben-Dor I, Goldstein SA, Pichard AD, et al. Clinical profile, prognostic implication, and response to treatment of pulmonary hypertension in patients with severe aortic stenosis. Am J Cardiol 2011; 107: 1046–51. 319 Review 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 320 O’Sullivan CJ, Wenaweser P, Ceylan O, et al. Effect of pulmonary hypertension hemodynamic presentation on clinical outcomes in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation: insights from the new proposed pulmonary hypertension classification. Circ Cardiovasc Interv 2015; 8: e002358. Mohammed SF, Hussain I, AbouEzzeddine OF, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014; 130: 2310–20. Sakata Y, Shimokawa H. Epidemiology of heart failure in Asia. Circ J 2013; 77: 2209–17. Bocchi EA, Braga FG, Ferreira SM, et al, and the Sociedasde Brasileira de Cardiologia. III Brazilian Guidelines on Chronic Heart Failure. Arq Bras Cardiol 2009; 93 (suppl 1): 3–70 (in Portuguese). Makubi A, Hage C, Lwakatare J, et al. Contemporary aetiology, clinical characteristics and prognosis of adults with heart failure observed in a tertiary hospital in Tanzania: the prospective Tanzania Heart Failure (TaHeF) study. Heart 2014; 100: 1235–41. Ogah OS, Sliwa K, Akinyemi JO, Falase AO, Stewart S. Hypertensive heart failure in Nigerian Africans: insights from the Abeokuta Heart Failure Registry. J Clin Hypertens (Greenwich) 2015; 17: 263–72. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012; 172: 1386–94. Stewart S, Wilkinson D, Hansen C, et al. Predominance of heart failure in the Heart of Soweto Study cohort: emerging challenges for urban African communities. Circulation 2008; 118: 2360–67. Bloomfield GS, Barasa FA, Doll JA, Velazquez EJ. Heart failure in sub-Saharan Africa. Curr Cardiol Rev 2013; 9: 157–73. Ntusi NB, Mayosi BM. Epidemiology of heart failure in sub-Saharan Africa. Expert Rev Cardiovasc Ther 2009; 7: 169–80. Stewart S, Mocumbi AO, Carrington MJ, Pretorius S, Burton R, Sliwa K. A not-so-rare form of heart failure in urban black Africans: pathways to right heart failure in the Heart of Soweto Study cohort. Eur J Heart Fail 2011; 13: 1070–77. Sliwa K, Davison BA, Mayosi BM, et al. Readmission and death after an acute heart failure event: predictors and outcomes in sub-Saharan Africa: results from the THESUS-HF registry. Eur Heart J 2013; 34: 3151–59. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromsø study. Heart 2013; 99: 396–400. Barreto-Filho JA, Wang Y, Dodson JA, et al. Trends in aortic valve replacement for elderly patients in the United States, 1999–2011. JAMA 2013; 310: 2078–85. Haub C. Population Reference Bureau. World population aging: clocks illustrate growth in population under age 5 and over age 65. http://www.prb.org/Publications/Articles/2011/ agingpopulationclocks.aspx (accessed June 20, 2015). Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5: 685–94. Zühlke L, Engel ME, Karthikeyan G, et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study). Eur Heart J 2015; 36: 1115–22a. Sriharibabu M, Himabindu Y, Kabir Z. Rheumatic heart disease in rural south India: A clinico-observational study. J Cardiovasc Dis Res 2013; 4: 25–29. Zhang W, Mondo C, Okello E, et al. Presenting features of newly diagnosed rheumatic heart disease patients in Mulago Hospital: a pilot study. Cardiovasc J Afr 2013; 24: 28–33. Sliwa K, Carrington M, Mayosi BM, Zigiriadis E, Mvungi R, Stewart S. Incidence and characteristics of newly diagnosed rheumatic heart disease in urban African adults: insights from the heart of Soweto study. Eur Heart J 2010; 31: 719–27. Sliwa K, Johnson MR, Zilla P, Roos-Hesselink JW. Management of valvular disease in pregnancy: a global perspective. Eur Heart J 2015; 36: 1078–89. Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006; 27: 397–412. 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Buist AS, McBurnie MA, Vollmer WM, et al, and the BOLD Collaborative Research Group. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007; 370: 741–50. Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev 2009; 18: 213–21. Menezes AM, Perez-Padilla R, Jardim JR, et al, and the PLATINO Team. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet 2005; 366: 1875–81. Adeloye D, Basquill C, Papana A, Chan KY, Rudan I, Campbell H. An estimate of the prevalence of COPD in Africa: a systematic analysis. COPD 2015; 12: 71–81. Uzaslan E, Mahboub B, Beji M, et al, and the BREATHE Study Group. The burden of chronic obstructive pulmonary disease in the Middle East and North Africa: results of the BREATHE study. Respir Med 2012; 106 (suppl 2): S45–59. Regional COPD Working Group. COPD prevalence in 12 Asia-Pacific countries and regions: projections based on the COPD prevalence estimation model. Respirology 2003; 8: 192–98. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006; 28: 523–32. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J, Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981; 36: 752–58. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE, and the National Emphysema Treatment Trial (NETT) Group. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002; 166: 314–22. Sims MW, Margolis DJ, Localio AR, Panettieri RA, Kawut SM, Christie JD. Impact of pulmonary artery pressure on exercise function in severe COPD. Chest 2009; 136: 412–19. Minai OA, Fessler H, Stoller JK, et al, and the NETT Research Group. Clinical characteristics and prediction of pulmonary hypertension in severe emphysema. Respir Med 2014; 108: 482–90. Cuttica MJ, Kalhan R, Shlobin OA, et al. Categorization and impact of pulmonary hypertension in patients with advanced COPD. Respir Med 2010; 104: 1877–82. Portillo K, Torralba Y, Blanco I, et al. Pulmonary hemodynamic profile in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2015; 10: 1313–20. Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest 1998; 113: 576–83. Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005; 127: 1531–36. Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172: 189–94. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32: 1371–85. Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest 1995; 107: 1193–98. Andersen KH, Iversen M, Kjaergaard J, et al. Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease. J Heart Lung Transplant 2012; 31: 373–80. US Census Bureau, International Data Base. World population by age and sex. http://www.census.gov/idb/worldpopinfo.html (accessed Aug 23, 2015). Ohno S, Nakaya T, Bando M, Sugiyama Y. Idiopathic pulmonary fibrosis—results from a Japanese nationwide epidemiological survey using individual clinical records. Respirology 2008; 13: 926–28. Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest 2010; 137: 129–37. Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11. Lancet Respir Med 2014; 2: 566–72. www.thelancet.com/respiratory Vol 4 April 2016 Review 121 Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol 2013; 5: 483–92. 122 Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 355–61. 123 Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746–52. 124 Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest 2007; 132: 998–1006. 125 Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 2007; 30: 715–21. 126 Rivera-Lebron BN, Forfia PR, Kreider M, Lee JC, Holmes JH, Kawut SM. Echocardiographic and hemodynamic predictors of mortality in idiopathic pulmonary fibrosis. Chest 2013; 144: 564–70. 127 Nathan SD, Shlobin OA, Ahmad S, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration 2008; 76: 288–94. 128 Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007; 131: 650–56. 129 Kimura M, Taniguchi H, Kondoh Y, et al. Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis. Respiration 2013; 85: 456–63. 130 Gläser S, Obst A, Koch B, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis—the predictive value of exercise capacity and gas exchange efficiency. PLoS One 2013; 8: e65643. 131 Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. Eur Respir J 2015; 46: 1370–77. 132 Corte TJ, Wort SJ, Gatzoulis MA, Macdonald P, Hansell DM, Wells AU. Pulmonary vascular resistance predicts early mortality in patients with diffuse fibrotic lung disease and suspected pulmonary hypertension. Thorax 2009; 64: 883–88. 133 Alhamad EH, Cal JG, Alfaleh HF, Alshamiri MQ, Alboukai AA, Alhomida SA. Pulmonary hypertension in Saudi Arabia: a single center experience. Ann Thorac Med 2013; 8: 78–85. 134 Moore LG, Niermeyer S, Zamudio S. Human adaptation to high altitude: regional and life-cycle perspectives. Am J Phys Anthropol 1998; 107 (suppl 27): 25–64. 135 Aldashev AA, Sarybaev AS, Sydykov AS, et al. Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med 2002; 166: 1396–402. 136 Sui GJ, Liu YH, Cheng XS, et al. Subacute infantile mountain sickness. J Pathol 1988; 155: 161–70. 137 Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 2007; 115: 1132–46. 138 Pasha MA, Newman JH. High-altitude disorders: pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 2010; 137 (suppl): 13S–19S. 139 Hoeper MM, Madani MM, Nakanishi N, Meyer B, Cebotari S, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Lancet Respir Med 2014; 2: 573–82. 140 Dentali F, Donadini M, Gianni M, et al. Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism. Thromb Res 2009; 124: 256–58. 141 Becattini C, Agnelli G, Pesavento R, et al. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 2006; 130: 172–75. 142 Pengo V, Lensing AW, Prins MH, et al, and the Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257–64. 143 Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography doppler and five-year survival analysis. Circulation 1999; 99: 1325–30. 144 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (suppl 1): I4–I8. www.thelancet.com/respiratory Vol 4 April 2016 145 Madani MM, Auger WR, Pretorius V, et al. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg 2012; 94: 97–103. 146 Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124: 1973–81. 147 Condliffe R, Kiely DG, Gibbs JS, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008; 177: 1122–27. 148 Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011; 141: 702–10. 149 Kawar B, Ellam T, Jackson C, Kiely DG. Pulmonary hypertension in renal disease: epidemiology, potential mechanisms and implications. Am J Nephrol 2013; 37: 281–90. 150 Sise ME, Courtwright AM, Channick RN. Pulmonary hypertension in patients with chronic and end-stage kidney disease. Kidney Int 2013; 84: 682–92. 151 Navaneethan SD, Roy J, Tao K, et al. Prevalence, predictors, and outcomes of pulmonary hypertension in CKD. J Am Soc Nephrol 2015; pii: ASN.2014111111. 152 Baughman RP, Engel PJ, Taylor L, Lower EE. Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest 2010; 138: 1078–85. 153 Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest 2006; 129: 1246–52. 154 Le Pavec J, Lorillon G, Jaïs X, et al. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012; 142: 1150–57. 155 Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161: 216–23. 156 Elstein D, Klutstein MW, Lahad A, Abrahamov A, Hadas-Halpern I, Zimran A. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 1998; 351: 1544–46. 157 den Bakker MA, Grünberg K, Boonstra A, van Hal PT, Hollak CE. Pulmonary arterial hypertension with plexogenic arteriopathy in enzyme-substituted Gaucher disease. Histopathology 2012; 61: 324–26. 158 Cottin V, Harari S, Humbert M, et al, and the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J 2012; 40: 630–40. 159 Lee TM, Berman-Rosenzweig ES, Slonim AE, Chung WK. Two cases of pulmonary hypertension associated with type III glycogen storage disease. JIMD Rep 2011; 1: 79–82. 160 Aliyu ZY, Kato GJ, Taylor J 6th, et al. Sickle cell disease and pulmonary hypertension in Africa: a global perspective and review of epidemiology, pathophysiology, and management. Am J Hematol 2008; 83: 63–70. 161 Piel FB, Patil AP, Howes RE, et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun 2010; 1: 104. 162 Huttle A, Maestre GE, Lantigua R, Green NS. Sickle cell in sickle cell disease in Latin America and the United States. Pediatr Blood Cancer 2015; 62: 1131–36. 163 Modell B, Darlison M, Birgens H, et al. Epidemiology of haemoglobin disorders in Europe: an overview. Scand J Clin Lab Invest 2007; 67: 39–69. 164 Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004; 350: 886–95. 165 Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 2011; 365: 44–53. 166 Mehari A, Alam S, Tian X, et al. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 2013; 187: 840–47. 167 Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J 2012; 39: 112–18. 321 Review 168 Castro O, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2003; 101: 1257–61. 169 Simonneau G, Parent F. Pulmonary hypertension in patients with sickle cell disease: not so frequent but so different. Eur Respir J 2012; 39: 3–4. 170 Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 2012; 307: 1254–56. 171 Du ZD, Roguin N, Milgram E, Saab K, Koren A. Pulmonary hypertension in patients with thalassemia major. Am Heart J 1997; 134: 532–37. 172 Farmakis D, Aessopos A. Pulmonary hypertension associated with hemoglobinopathies: prevalent but overlooked. Circulation 2011; 123: 1227–32. 173 Derchi G, Galanello R, Bina P, et al, and the Webthal Pulmonary Arterial Hypertension Group. Prevalence and risk factors for pulmonary arterial hypertension in a large group of β-thalassemia patients using right heart catheterization: a Webthal study. Circulation 2014; 129: 338–45. 174 Aessopos A, Stamatelos G, Skoumas V, Vassilopoulos G, Mantzourani M, Loukopoulos D. Pulmonary hypertension and right heart failure in patients with beta-thalassemia intermedia. Chest 1995; 107: 50–53. 322 175 Aessopos A, Farmakis D, Deftereos S, et al. Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia. Chest 2005; 127: 1523–30. 176 Meloni A, Detterich J, Pepe A, Harmatz P, Coates TD, Wood JC. Pulmonary hypertension in well-transfused thalassemia major patients. Blood Cells Mol Dis 2015; 54: 189–94. 177 Aessopos A, Farmakis D, Hatziliami A, et al. Cardiac status in well-treated patients with thalassemia major. Eur J Haematol 2004; 73: 359–66. 178 Crary SE, Ramaciotti C, Buchanan GR. Prevalence of pulmonary hypertension in hereditary spherocytosis. Am J Hematol 2011; 86: E73–76. 179 Jaïs X, Ioos V, Jardim C, et al. Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 2005; 60: 1031–34. 180 Population Reference Bureau. World population aging: clocks illustrate growth in population under age 5 and over age 65. http://www.prb.org/Publications/Articles/2011/ agingpopulationclocks.aspx (assessed June 20, 2015). 181 Feuer EJ, Wun LM, Boring CC, Flanders WD, Timmel MJ, Tong T. The lifetime risk of developing breast cancer. J Natl Cancer Inst 1993; 85: 892–97. 182 Humbert M, Lau EM, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014; 130: 2189–208. www.thelancet.com/respiratory Vol 4 April 2016